Preclinical Efficacy Results

Multiple preclinical in vivo studies have confirmed the potential of P-188 NF to address:

  • Cardiac and respiratory dysfunction in animal models of DMD;
  • Skeletal limb muscle weakness in animal models of DMD and limb girdle muscular dystrophy; and
  • Cardiac dysfunction in animal models of heart failure in the general population.

Confirmation that P-188 NF protects skeletal limb muscle in animal model of DMD when administered subcutaneously, but not intravenously or peritoneally.
Houang EM, Haman KJ, Filareto A, Perlingeiro RC, Bates, FS, Lowe, DA, Metzger, JM. Membrane-stabilizing copolymers confer marked protection to dystrophic skeletal muscle in vivo. Molecular Therapy — Methods & Clinical Development 2, Article number: 15042 (2015) ​doi:10.1038/mtm.2015.42.

Jason Celik

Jason Celik

Independent confirmation of hypothesized mechanism of action for Carmeseal-MD™ (P-188 NF) as membrane sealant on dystrophic cells.
Lin B, Li Y, Han L, Kaplan AD, Ao Y, Kalra S, Bett GC, Rasmusson RL, Denning C, Yang L. Modeling and study of the mechanism of dilated cardiomyopathy using induced pluripotent stem cells derived from individuals with Duchenne muscular dystrophy. Dis Model Mech. 2015 May;8(5):457-66. doi: 10.1242/dmm.019505. Epub 2015 Mar 19.

Demonstration of respiratory and cardiac benefits of P-188 NF in mdx and mdx/utr double knock-out mouse models of DMD after subcutaneous dosing at 1 mg/Kg.
Markham BE, Kernodle S, Nemzek J, Wilkinson JE, Sigler R. Chronic dosing with membrane sealant Poloxamer 188 NF improves respiratory dysfunction in dystrophic mdx and mdx/utrophin-/- mice. 2015. PLoS ONE 10(8): e0134832. doi:10.1371/journal.pone.0134832.

Treatment with P-188 NF improves the LV function and partially reverses maladaptive LV remodeling in rats with moderate CHF after MI.
Juneman EB, Saleh L, Lancaster JJ, Thai HM, Markham B, and Goldman S. The effects of Poloxamer-188 on left ventricular function in chronic heart failure after myocardial infarction. J Cardiovasc Pharmacol. 2012; 60: 293-298.

Independent confirmation of cardiac benefit of P-188 NF in mdx mice.
Spurney CF, Guerron AD, Yu Q, Sali A, van der Meulen JH, Hoffman EP, Nagaraju, K. Membrane sealant poloxamer P188 protects against isoproterenol induced cardiomyopathy in dystrophin deficient mice. BMC Cardiovasc. Disorders 2011 11: 20-30.

Independent confirmation that subcutaneously administered P-188 NF has a protective effect on skeletal limb muscle in a mouse model of limb girdle muscular dystrophy.
Suzuki N., Akiyama, T., Takahashi T., Komuroa H., Waritaa H., Tateyamaa M, Itoyamac, Y., Aokia M. 2011. Continuous administration of poloxamer 188 reduces overload-induced muscular atrophy in dysferlin-deficient SJL mice. Neurosci. Res., doi:10.1016/j.neures. 2011.10.005.

Chronic administration of P-188 NF prevents cardiac remodeling in dystrophic dogs.
Townsend D, Turner I, Yasuda S, Martindale J, Davis J, Shillingford M, Kornegay JN, Metzger JM. Chronic administration of membrane sealant prevents severe cardiac injury and ventricular dilatation in dystrophic dogs. J Clin Invest. 2010, 120:1140-1150.

Bolus injection of P-188 NF improves left ventricular function in dogs with heart failure.
Ilsar, I., Wang, M., Jiang, A., Dye, K., Markham, B., Sabbah, H.N. (2010) Acute intravenous bolus injection of Poloxamer-188 improves left ventricular function in dogs with heart failure J. Am. Col. Cardiol. 55 (Suppl. 1): A16.E146.

P-188 NF reduces the contraction-induced force decline in lumbrical muscle from mdx mice.
Ng R, Metzger JM, Claflin DR, Faulkner JA. 2008. Poloxamer 188 reduces the contraction-induced force decline in lumbrical muscles from mdx mice. Am J Physiol Cell Physiol 295: C146–150.

Independent confirmation: P-188 NF reduces membrane permeability in tibialis anterior muscle from dystrophic mdx mice
Ryall JG, van der Poel C, Schertzer JD, Plant DR, Lynch GS, The membrane sealant poloxamer reduces membrane permeability in tibialis anterior muscles from dystrophic mdx mice. The FASEB Journal. 2007;21:769.28.

Independent confirmation: P-188 NF helps maintain sarcolemmal integrity in the mdx dystrophic mouse tibialis anterior muscles
Plant DR, Ryall JG, Lynch GS. Contraction-mediated damage in mdx dystrophic mouse tibialis anterior muscles is not affected by the membrane sealant poloxamer Proc. Australia Physiological Society. 2005; 36: 133P (abstract).

Proof of concept that P-188 NF can seal membranes and block heart failure in mdx mice.
Yasuda S, Townsend D, Michele DE, Farve EG, Day SM, Metzger J. Dystrophic heart failure blocked by membrane sealant poloxamer. Nature 2005 436: 1025-1029.

 

In related models (not DMD animal models), seven independent studies showed:

Watanabe & Okada, 2003, demonstrated that P-188 NF has a protective affect on isolated heart (rat)
Watanabe M, Okada T. Lysophosphatidylcholine-induced myocardial damage is inhibited by pretreatment with poloxamer 188 in isolated rat heart. Mol Cell Biochem. 2003; 248:209-215.

Six additional papers demonstrated positive effects of P-188 NF on skeletal muscle both in vivo and in vitro

Walters TJ, Mase VJ Jr, Roe JL, Dubick MA, Christy RJ. Poloxamer-188 reduces muscular edema after tourniquet-induced ischemia-reperfusion injury in rats. J Trauma. 2011; 70:1192-1197.

Murphy AD, McCormack MC, Bichara DA, Nguyen JT, Randolph MA, Watkins MT, Lee RC, Austen WG Jr. Poloxamer 188 protects against ischemia-reperfusion injury in a murine hind-limb model. Plast Reconstr Surg. 2010; 125:1651-1660.

Greenebaum B, Blossfield K, Hannig J, Carrillo CS, Beckett MA, Weichselbaum RR, Lee RC. Poloxamer 188 prevents acute necrosis of adult skeletal muscle cells following high-dose irradiation. Burns. 2004: 30:539-547.

Hannig J, Zhang D, Canaday DJ, Beckett MA, Astumian RD, Weichselbaum RR, Lee RC. Surfactant sealing of membranes permeabilized by ionizing radiation. Radiat Res. 2000; 154:171-177.

Padanilam JT, Bischof JC, Lee RC, Cravalho EG, Tompkins RG, Yarmush ML, Toner M. Effectiveness of poloxamer 188 in arresting calcein leakage from thermally damaged isolated skeletal muscle cells. Ann N Y Acad Sci. 1994; 720:111-123.

Lee RC, River LP, Pan FS, Ji L, Wollmann R L (1992). Surfactant-induced sealing of electropermeabilized skeletal muscle membranes in vivo. Proc. Natl. Acad. Sci. U. S. A 89:4524-4528.